Autologous bone marrow transplanation for extramedullary plasmacytoma presenting as adrenal incidentaloma

Extramedullary adrenal plasmacytoma (EMP) involving the adrenal glands is rarely encountered clinicaly. We report a A 47-year-old male who presented with bilateral adrenal incidentalomas. After confirming EMP, the patient received two consecutive autologous hematopoietic stem cell transplants (HSCT) using high-dose melphalan. Following HSCT, a serial follow-up helical CT revealed a substantial decrease in the size of both adrenal masses. Serial periodic serum protein and urine electrophoresis and immunofixation showed abrogation of a previously noted monoclonal band. At 50 months follow-up the patient was alive and well. Our patient is the first with EMP to have received an autologous HSCT, which may prove to have a role in therapy due to the immunological effect of the infused donor marrow T-lymphocytes against the clonal proliferation of abnormal plasma cells in extrammedullary sites. This case indicates that an EMP should be added to the differential diagnosis of adrenal incidentalomas.

P lasmacytomas are tumors that arise in different locations due to the ubiquitous tissue distribut t tion of plasma cells. They are a clonal prolift t eration of atypical plasma cells that exhibit a localized osseous or extraosseous (extramedullary) growth patt t tern. 1 Extramedullary plasmacytomas (EMPs) have been described in a variety of locations. 1 EMP involving the adrenal gland is unusual. In reporting the case, we wish to draw attention to its possibility in the different t tial diagnosis of adrenal incidentalomas.

CASE
A 47tyeartold male presented at an outside hospital with painful right hip that was diagnosed as synovitis of the hip. A CT scan of the hip that included the abt t domen detected bilateral adrenal masses. At presentat t tion he was totally asymptomatic and other than large palpable bilateral abdominal flank masses had a totally negative physical examination. The patient underwent the following investigations: hemoglobin 149 g/L, red blood cells 5.37×10 12 /L, WBC 6.1×10 9 /L, serum cret t atinine 87 µmol/L (reference range, 65t129 µmol/L) set t Extramedullary adrenal plasmacytoma (EMP) involving the adrenal glands is rarely encountered clinical-ly. We report a A 47-year-old male who presented with bilateral adrenal incidentalomas. After confirm-ing EMP, the patient received two consecutive autologous hematopoietic stem cell transplants (HSCT) using high-dose melphalan. Following HSCT, a serial follow-up helical CT revealed a substantial de-crease in the size of both adrenal masses. Serial periodic serum protein and urine electrophoresis and immunofixation showed abrogation of a previously noted monoclonal band. At 50 months follow-up the patient was alive and well. Our patient is the first with EMP to have received an autologous HSCT, which may prove to have a role in therapy due to the immunological effect of the infused donor marrow T-lymphocytes against the clonal proliferation of abnormal plasma cells in extrammedullary sites.This case indicates that an EMP should be added to the differential diagnosis of adrenal incidentalomas. rum calcium 1.95t2.25 g/L (reference range, 2.10t2.55 g/L), serum albumin 35 g/L (reference range, 42t48 g/L), serum phosphorus 0.57t1.27 mmol/L (reference range, 0.7t1.45 mmol/L), alkaline phosphatase 64t 96 U/L (reference range, 40t115 U/L), total proteins 109 g/L (reference range, 65t81 g/L), and urine total protein of 1.22 g/L. The hormonal profile consisted of 24thour urine normetanephrines of 2.88 µmol/day (reference range, 0t3.43 µmol), urine metanephrines of 0 µmol/day (reference range, 0t1.49), urine 3tmethoxyt t tyramine 1.34 µmol/day (reference range, 0t2.06), synthetic ACTH stimulation testing revealed a nort t mal adrenal cortical reserve (base line serum cortisol, 301 nmol/L that increased to a peak of 564.7 nmol/L at one hour following intramuscular administration of 250 µg of 1t24 synthetic ACTH), urine cortisol of 45 µg/day (reference range, <100 µg/day), urine aldostet t rone <33 nmol/day (reference range, 8t83 nmol/day), supine renin of 2.17 µg/L/h (reference range, 0.15t2.33 µg/L/h), and serum dehydroepiandrosterone sulfate of 0.7 µmol/L (reference range, 1.2t8.71). Imaging data consisted of an ultrasound of the abdomen/pelvis (not shown) that revealed large bilateral adrenal masses, a CT of the abdomen (Figure 1a without contrast and figure 1b following contrast administration) and an MRI abdomen (not shown) that showed massive bilateral adrenal masses, displacing the kidneys infet t riorly, but that was otherwise negative. A skeletal surt t vey (ribs, clavicle, scapulae, skull, spine, long bones of upper and lower extremities, pelvis), whole body bone scan and MRI spine showed no findings suggestive of multiple myeloma. Ultrasoundtguided fine needle ast t piration biopsy of the right adrenal mass ( Figure 2a) and a coretneedle biopsy (Figure 2b) showed mort t phological findings consistent with the diagnosis of plasmacytoma. Immunohistochemical staining data (Figures 2c and 2d) supported the diagnosis of plast t macytoma. Flow cytometry analysis of the adrenal tumor revealed an abnormal CD38+ cell population that exhibited monoclonal cytoplasmic kappa light chain expression, but negative for CD45, cytokeratin and lambda light chain ( Figure 3). A bone marrow ast t pirate showed normocellular pattern with no evidence of multiple myeloma. Bone marrow flow cytometry for leukemia/lymphoma markers was negative. A distinct monoclonal protein band accounting for 44.6% of tot t tal serum proteins and 87.9% total gamma globulins was shown on serum protein electrophoresis. (Figure  4a) . Immunofixation electrophorisis of urine specit t men demonstrated free kappa light chain (Bence Jones proteins) (Figure 4b).
At initial treatment the patient received chet t motherapy consisting of two cycles of vincristine, Adriamycin and dexamethasone (VAD) followed by two cycles of etoposide, dexamethasone, AratC and cisplatinum (EDAP). A followtup CT scan showed no change in the size of the bilateral adrenal lesions nor was there a change in the immunological studies of serum and urine. Two years following initial present t tation the patient received two consecutive autologous hematopoietic stem cell transplantation (HSCT) prot t cedures using high dose melphalan. Starting 6 months posttHSCT through a last followtup at 50 months, serial periodic serum protein electrophoresis and immunofixation showed abrogation of a previously noted monoclonal band. Urine electrophoresis and urine immunofixation also turned out to be negative for BencetJones proteins. A last CT scan of the abdot t men done at 47 month followtup (Figure 1b

DISCUSSION
The diagnosis in our case was based on the findings of a plasma cell tumor in an extramedullary site detected on adrenal imaging, the tissue diagnosis, the relevant immunological analysis of serum and urine, flow cyt t tometry of the adrenal tumor, the absence of mutiple myeloma on bone marrow examination and the absence of skeletal lesions, coupled with the longtterm followt up data. An EMP is a rare malignant tumor. Fewer than 3% of all plasma cell proliferative disorders are EMPs. 2 In the majority of instances (80% of cases), they occur in the upper respiratory tract or the oral cavity. 3 The ret t mainder arise in the gastrointestinal tract, central nert t vous system, breast, spleen, retroperitoneum, testes, and the thyroid or the lymph nodes. 3 Extramedullary plasmacytoma involving the adrenal gland is unusual. It has been reported in 4 other cast t es previously. 3t6 Three of these cases were reported in middletaged Japenese men presenting as adrenal incit t dentaloma who had an IgG monoclonal spike that was characterized as lambda light chain on immunoelect t trophoresis. 3t5 In previously reported cases the adrenal plasmacytomas were all unilateral righttsided lesions and compared to our case were relatively smaller in size (3.5t4 cm). 3t6 All were hormonally nontfunctioning 3t6 as was our case and their followtup data extended up to a year. Fujikata et al have reported no tumor recurrence after a year of followtup following surgical excision and radiotherapy. 5 Laproscopic adrenalectomy was done in 3 other cases reported by Kahara et al, 3 Asahi et al, 4 and Rogers et al. 6 In contrast to previously reported cases, our case is dintinct in presenting with bilateral incidentalomas that were much larger, producing IgG kappa light chain, followedtup for a longer time period without surgical intervention but received chemotherapy that was cont t sidered a failure and had then undergone two cont t secutive autologous HSCT procedures. Following the first HSCT patient demonstrated a partial reduction of the adrenal masses and an improvement in protein electrophoresis. Considering these responses, a second HSCT procedure was undertaken that was temporally related to a significant reduction in the tumor size and resolution of the abnormal findings in serum and urine electrophoresis. These responses remained sustained without maintenance therapy. Because a biopsy was not performed from the contralateral left adrenal mass, we cannot definitely state that our patient indeed had bit t lateral plasmacytomas. However, the imaging findings, the followtup data and the regression in the size simit t lar to that of the right adrenal plasmacytoma following HSCT is highly suggestive of a bilateral process.    . Note the distinct monoclonal protein peak (1) on cZe-Spe in the γ region, that is removed from the electrophoresis pattern by antisera to gamma (2) heavy chains (anti-IgG) and kappa light chains (3). the antisera to IgG lambda, IgA, and IgM had no effect (lower panel). the immunosubtraction indicated the monoclonal protein is IgG Kappa. (B) Immunofixation electrophoresis (IFe) of urine specimen for Bence-Jones protein (BJp) using Beckman paragon system. Note the dense band of free kappa light chains corresponding to the band seen on urine protein electrophoresis (upe). Note also the prozone effect (antigen excess) using 1:5 dilution, and its disappearance using 1:10 dilution.
The role of HSCT in the management of EMPs is not defined. For the last 20 years autologus and alt t logeneic HSCT have been used to advantage in pat t tients with multiple myeloma. 7,8 However, there is no previous experience whatsoever regarding the use of HSCT in the management of adrenal plasmacytoma. Our patient with extramedullary plasmacytoma of the adrenal is the first to have received an autologous HSCT. HSCT may have a potential role, probably due to an immunological effect of the infused donor's marrow Ttlymphocytes against the clonal proliferat t tion of abnormal plasma cells in extrammedullary sites. We remain cautiously optimistic on the impact of consecutive autologous HSCT in EMP in our pat t tient. Unquestionably, more experience is needed to study the effect of HSCT in extramedullary EMPs in general.
In conclusion, although the frequency of diagnot t sis of adrenal incidentaloma has increased with the increased use of contemporary imaging modalities, the definitive diagnosis of such lesions should rest on a combination of clinical and pertinent laboratory criteria coupled with cytological/histological criteria. Thorough investigations will lead to the diagnosis of most unusual adrenal lesions, which can have an enort t mous impact on treatment, quality of life and on event t tual outcome. EMP should be considered among the differential diagnoses of adrenal incidentalomas.